A. Specific Aims This project will concern the properties and biological applications of peptides that interact with membranes or with the extracellular matrix. We seek new information and new understanding of peptide/lipid interactions and peptide/matrix interactions. We seek to apply some of this information to develop potential new strategies for treating Clostridium infections. Two of our systems of investigation will be drawn from Clostridium, while a third fundamental approach will use a model system to explore peptide folding within a lipid environment. The specific aims are these: 1. To understand peptide transport across membranes and the preferential use of low M/T peptides by Clostridium difficile for growth and colonization. 2. To elucidate general principles that govern the folding and biological function of membrane-spanning proteins. 3. To understand the mechanisms by which the extracellular matrix is recognized by a collagen-binding domain (CBD) from Clostridium histolyticum, and to develop peptides that could mimic the CBD. Such peptides would then be fused to autocrine/paracrine factors such as growth for the development of a wide range of novel therapeutic agents with potential clinical applications.